This invention relates to novel phenoxyacetic acid derivatives, compositions containing them, processes and intermediates for their preparation, and their use as herbicides.
Japanese Patent Publication No. Sho 62-48649 discloses the preparation and fungicidal or plant growth regulator activity for the following acrylic acid ester derivatives, stereoisomers thereof, and metal complexes of general formula: 
wherein, Vxe2x80x2 represents an oxygen or sulfur atom; Xxe2x80x2 and Yxe2x80x2, may be the same or different selected from a hydrogen or halogen atom, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroring, optionally substituted alkynyl, haloalkyl, alkoxy, optionally substituted haloalkoxy, optionally substituted arylalkoxy, optionally substituted acyloxy, optionally substituted amino, acylamino, nitro, nitrile, xe2x80x94CO2R3xe2x80x2, xe2x80x94CONR4xe2x80x2R5xe2x80x2, or xe2x80x94COR6xe2x80x2 group, or Xxe2x80x2 and Yxe2x80x2 being at the adjacent position on a phenyl ring, may form an aromatic condensed ring or an aliphatic condensed ring optionally containing one or more hetero atoms; Zxe2x80x2 represents optionally substituted methylene, optionally substituted amino, oxygen or sulphur and when Zxe2x80x2 is a substituted methylene group, the substituent may join the 2-position of the phenyl ring to form a non-aromatic fused ring; R1xe2x80x2 and R2xe2x80x2 each independently represent an alkyl group having from one to four carbon atoms optionally substituted by one or more halogen atoms; R3xe2x80x2, R4xe2x80x2, R5xe2x80x2 and R6xe2x80x2 are the same or different groups selected from a hydrogen atom, optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted aralkyl and cycloalkyl. However it has not been disclosed or suggested that any 3-alkoxy-2-phenoxyacrylate derivatives having a substituted alkyl substituent(in particular a haloalkyl or hydroxyalkyl substituent) on the benzene ring possess useful herbicidal properties.
It is an object of the invention to provide new phenoxyacetic acid derivatives useful as herbicides, and processes for their preparation.
A second object of the invention is to provide herbicidal compositions and herbicidal methods of use for herbicidal phenoxyacetic acid derivatives.
A third object of the invention is to provide phenoxyacetic acid derivatives which possess selective herbicidal activity.
A fourth object of the invention is to provide phenoxyacetic acid derivatives effective as low dose herbicides.
A fifth object of the invention is to provide phenoxyacetic acid derivatives which possess good residual activity.
These and other objects of the invention can be achieved in whole or in part.
The present invention provides phenoxyacetic acid derivatives of formula 
wherein:
R1 and R2 each represents independently a hydrogen atom, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl or xe2x80x94CmH2m (optionally substituted phenyl);
X represents a halogen atom, cyano, lower alkoxycarbonyl, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, lower alkoxy, lower alkylthio, lower alkylsulphinyl, lower alkylsulfonyl, lower haloalkoxycarbonyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, halocycloalkyl, lower haloalkoxy, lower haloalkylthio, lower haloalkylsulphinyl, lower haloalkylsulfonyl, nitro, amino, lower alkylamino, lower dialkylamino, optionally substituted phenoxy, lower alkylcarbonylamino, carbamoyl, lower alkylcarbamoyl, lower dialkylcarbamoyl or SF5;
n and m represent 0, 1 or 2;
A represents halogen atom, hydroxy, or Axe2x80x2 wherein Axe2x80x2 represents OR3, S(O)KR3; or represents a formula II: 
R3 represents optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted lower alkylcarbonyl, optionally substituted lower alkenylcarbonyl, optionally substituted lower alkynylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted phenylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted cycloalkenyl, optionally substituted cycloalkenylcarbonyl, xe2x80x94CpH2p (optionally substituted phenyl), xe2x80x94CqH2q (optionally substituted heteroaryl), xe2x80x94(CrH2r) CO2alkyl, xe2x80x94(CsH2s) cycloalkyl, xe2x80x94CO(CtH2t)Y, xe2x80x94(CuH2u) COCH2 (optionally substituted phenyl), xe2x80x94(CfH2f) O (optionally substituted phenyl), xe2x80x94(CgH2g) S (optionally substituted phenyl), or xe2x80x94(CjH2j) O (CzH2z) (optionally substituted phenyl);
k represents zero, one or two;
f, g, j, z, p, q, r, s, t and u represent one or two;
Y represents optionally substituted phenyl, optionally substituted phenoxy, optionally substituted heteroaryl, optionally substituted phenylthio, alkoxy or optionally substituted heteroaryloxy;
R4 represents a hydrogen atom, cyano, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted phenyl, or optionally substituted heteroaryl;
R5 represents optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted lower alkoxy, optionally substituted lower alkenyloxy, optionally substituted lower alkynyloxy, optionally substituted cycloalkyloxy, optionally substituted heteroaryloxy, optionally substituted cycloalkenyloxy, , optionally substituted heteroaryl, xe2x80x94CvH2v (optionally substituted phenyl), xe2x80x94OCwH2w (optionally substituted phenyl), xe2x80x94(CxH2x) O (optionally substituted phenyl), optionally substituted lower alkylthio, optionally substituted phenylthio, xe2x80x94SCyH2y (optionally substituted phenyl) or optionally substituted phenoxy;
v, w, x and y represent one or two;
a geometric isomer thereof;
and agriculturally acceptable salts thereof, which possess valuable herbicidal properties.
In the phenoxyacetic acid derivatives of the present invention, there are two different stereoisomers, syn and anti [in other words, cis (Z), and trans (E) isomers] at a double bond. It will be understood that the present invention embraces both the pure isomers and mixtures thereof.
In certain cases the substituents R1, R2, R3, R4, R5, A and X contribute to optical isomerism and/or stereo isomerism. All such forms are embraced by the present invention.
By the term xe2x80x9cagriculturally acceptable saltsxe2x80x9d is meant salts the cations or anions of which are known and accepted in the art for the formation of salts for agricultural or horticultural use. Preferably the salts are water-soluble. Suitable salts with bases, include alkali metal (e.g. sodium and potassium), alkaline earth metal (e.g. calcium and magnesium), ammonium and amine (e.g. diethanolamine, triethanolamine, octylamine, morpholine and dioctylmethylamine) salts. Suitable acid addition salts, e.g. formed by compounds of formula I containing an amino group, include salts with inorganic acids, for example hydrochlorides, sulphates, phosphates and nitrates and salts with organic acids for example acetic acid.
It is understood that in the above definitions used in formula (I) all of the optionally substituted groups may have as the optional substituent one or more halogen atoms.
It is also understood that for optionally substituted cycloalkyl, optionally substituted cycloalkenyl and for other optionally substituted groups which incorporate cycloalkyl or cycloalkenyl portions, the optional substituent may be selected from lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl and halogen.
It is also understood that for optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted phenoxy, optionally substituted phenylthio, optionally substituted phenylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted heteroaryloxy, and other optionally substituted groups which incorporate phenyl or heteroaryl portions, that the optional substituent is selected from halogen, phenoxy, lower alkyl, lower haloalkyl, cyano, lower alkoxycarbonyl, lower haloalkoxycarbonyl, lower alkoxy, lower haloalkoxy, lower alkylthio, lower haloalkylthio, lower alkylsulfinyl, lower haloalkylsulfinyl, lower alkylsulfonyl, lower haloalkylsulfonyl, nitro, alkylcarbonyl, lower alkylamino, lower dialkylamino, carbamoyl, lower alkylcarbamoyl, lower dialkylcarbamoyl and lower alkylcarbonylamino.
In the present invention, some embodiments of A, Axe2x80x2, R2, R3, R4, R5, and X defined previously will be explained more precisely as follows.
Halogen atom means fluorine, chlorine, bromine or iodine.
Lower alkyl means a straight- or branched-chain alkyl group having from one to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, tert-pentyl or hexyl.
Lower alkenyl means a straight- or branched-alkenyl group having from two to six carbon atoms, such as ethenyl, propenyl, butenyl or pentenyl.
Lower alkynyl means a straight- or branched-chain alkynyl group having from two to six carbon atoms, such as ethynyl, propynyl, butynyl, pentynyl or hexynyl.
Cycloalkyl groups have from three to six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Cycloalkenyl groups have five or six carbon atoms namely cyclopentenyl or cyclohexenyl.
Lower alkoxy groups contain from one to six carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy or pentoxy.
Lower alkenyloxy groups have from two to six carbon atoms, such as ethenyloxy, propenyloxy, butenyloxy or pentenyloxy.
Lower alkynyloxy groups have from two to six carbon atoms, such as ethynyloxy, propynyloxy, butynyloxy, pentynyloxy or hexynyloxy.
Cycloalkyloxy groups have from three to six carbon atoms, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy.
Cycloalkenyloxy groups have five or six carbon atoms, namely cyclopentenyloxy or cyclohexenyloxy.
Lower alkylthio groups contain from one to six carbon atoms, for example methylthio, ethylthio, propylthio, isopropylthio, butylthio or pentylthio.
Lower alkylsulphinyl groups have from one to six carbon atoms, for example methylsulphinyl, ethylsulphinyl, propylsulphinyl, isopropylsulphinyl, butylsulphinyl or pentylsulphinyl.
Lower alkylsulfonyl groups have from one to six carbon atoms, for example methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl or pentylsulfonyl.
Lower alkylcarbonyl groups contain from one to six carbon atoms in the alkyl portion, such as methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl or pentylcarbonyl.
Lower alkenylcarbonyl groups contain from two to six carbon atoms in the alkenyl portion; for example, ethenylcarbonyl, propenylcarbonyl, butenylcarbonyl or pentenylcarbonyl.
Lower alkynylcarbonyl groups contain from two to six carbon atoms in the alkynyl portion, for example, ethynylcarbonyl, propynylcarbonyl, butynylcarbonyl, pentynylcarbonyl or hexynylcarbonyl.
Cycloalkylcarbonyl groups contain from three to six carbon atoms in the cycloalkyl portion, for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl or cyclohexylcarbonyl.
Cycloalkenylcarbonyl groups contain five or six carbon atoms in the cycloalkenyl portion, namely cyclopentenylcarbonyl or cyclohexenylcarbonyl.
Lower haloalkyl groups contain from one to six carbon atoms, such as bromomethyl, difluoromethyl, dichloromethyl, trifluoromethyl, 1-chloroethyl, 2-iodoethyl, 3-chloropropyl, 2-methyl-2-chloropropyl or 2,2,2-trifluoroethyl.
Lower haloalkoxy groups contain from one to six carbon atoms, for example, trifluoromethoxy, difluoromethoxy, chlorodifluoromethoxy, 2-chloroethoxy, 1,1,2,2-tetrafluoroethoxy or 3-chloropropoxy.
Lower haloalkylthio groups contain from one to six carbon atoms, for example trifluoromethylthio, difluoromethylthio, chlorodifluoromethylthio, 2-chloroethylthio, 1,1,2,2-tetrafluoroethylthio or 3-chloropropylthio.
Lower haloalkylsulphinyl groups contain from one to six carbon atoms, for example, trifluoromethylsulphinyl, difluoromethylsulphinyl, chlorodifluoromethylsulphinyl, 2-chloroethylsulphinyl, 1,1,2,2-tetrafluoroethylsulphinyl or 3-chloropropylsulphinyl.
Lower haloalkylsulfonyl groups contain from one to six carbon atoms, for example, trifluoromethylsulfonyl, difluoromethylsulfonyl, chlorodifluoromethylsulfonyl, 2-chloroethylsulfonyl, 1,1,2,2-tetrafluoroethylsulfonyl or 3-chloropropylsulfonyl.
Lower alkoxycarbonyl groups contain from one to six carbon atoms in the alkoxy portion, for example, methoxycarbonyl, ethoxycarbonyl or isopropylcarbonyl.
Lower haloalkoxycarbonyl groups contain from one to six carbon atoms in the alkoxy portion, for example, trifluoromethoxycarbonyl, difluoromethoxycarbonyl, chlorodifluoromethoxycarbonyl, 2-chloroethoxycarbonyl, 1,1,2,2-tetrafluoroethoxycarbonyl or 3-chloropropoxycarbonyl.
Heteroaryl groups comprise a five or six membered aromatic heterocyclic ring containing from one to three hetero atoms selected from oxygen, nitrogen and sulphur, for example, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, pyridyl, pyrimidyl or pyridazinyl.
Heteroaryloxy groups comprise as the heteroaryl portion a five or six membered heterocyclic ring containing from one to three hetero atoms selected from oxygen, nitrogen and sulphur, for example, furanyloxy, thienyloxy, pyrrolyloxy, pyrazolyloxy, imidazolyloxy, thiazolyloxy, pyridyloxy, pyrimidyloxy or pyridazinyloxy.
Heteroarylthio groups comprise as the heteroaryl portion a five or six membered heterocyclic ring containing from one to three hetero atoms selected from oxygen, nitrogen and sulphur, for example, furanylthio, thienylthio, pyrrolylthio, pyrazolylthio, imidazolylthio, thiazolylthio, pyridylthio, pyrimidylthio or pyridazinylthio.
In addition, any group not cited above can be obtained by combination of the above atoms or groups, or by selecting from atoms or groups known per se.
Compounds of formula (I) above in which the group CH2A is located at the ortho position of the phenyl ring are preferred.
Compounds of formula (I) above in which R1 and R2 represent lower alkyl are preferred (preferably R1 and R2 represent methyl).
Compounds of formula (I) above in which X represents halogen are preferred (compounds wherein X is chlorine are especially preferred).
Compounds of formula (I) above in which A represents a group selected from halogen; hydroxy; A-1 wherein R4 represents lower alkyl and R5 represents xe2x80x94OCwH2w (optionally substituted phenyl), optionally substituted phenoxy or lower alkyl; OR3 wherein R3 represents optionally substituted phenyl, optionally substituted lower alkylcarbonyl or lower alkyl; A-2 wherein R4 represents lower alkyl and R5 represents xe2x80x94OCH2 (optionally substituted phenyl); and SR3 wherein R3 represents optionally substituted phenyl, CH2 (optionally substituted phenyl), lower alkyl or cycloalkyl, are preferred (compounds in which A represents halogen or hydroxy are especially preferred).
Preferably the compounds of formula (I) are Z isomers at the double bond which is substituted by OR1.
A preferred class of compounds of formula (I) are those wherein:
R1 and R2 represent lower alkyl;
the group CH2A is located at the ortho position of the phenyl ring; and
A represents a group selected from halogen; hydroxy; A-1 wherein R4 represents lower alkyl and R5 represents xe2x80x94OCwH2w (optionally substituted phenyl), optionally substituted phenoxy or lower alkyl; OR3 wherein R3 represents optionally substituted phenyl, optionally substituted lower alkylcarbonyl or lower alkyl; A-2 wherein R4 represents lower alkyl and R5 represents xe2x80x94OCH2 (optionally substituted phenyl); and SR3 wherein R3 represents optionally substituted phenyl, xe2x80x94CH2 (optionally substituted phenyl), lower alkyl or cycloalkyl.
A further preferred class of compounds of formula (I) are those wherein:
R1 and R2 represent lower alkyl;
X represents halogen; and
CH2A is located at the ortho position of the phenyl ring and A represents a group selected from halogen; hydroxy; A-1 wherein R4 represents lower alkyl and R5 represents xe2x80x94OCwH2w (optionally substituted phenyl), optionally substituted phenoxy or lower alkyl; OR3 wherein R3 represents optionally substituted phenyl, optionally substituted lower alkylcarbonyl or lower alkyl;
A-2 wherein R4 represents lower alkyl and R5 represents xe2x80x94OCH2 (optionally substituted phenyl); and SR3 wherein R3 represents optionally substituted phenyl, xe2x80x94CH2 (optionally substituted phenyl), lower alkyl or cycloalkyl.
A further preferred class of compounds of formula (I) are those wherein:
R1 and R2 represent lower alkyl;
X represents halogen;
CH2A is located at the ortho position of the phenyl ring; and
A represents a group selected from halogen; hydroxy; A-1 wherein R4 represents lower alkyl and R5 represents xe2x80x94OCH2 (optionally substituted phenyl), optionally substituted phenoxy or lower alkyl; OR3 wherein R3 represents optionally substituted phenyl, lower alkylcarbonyl or lower alkyl; and A-2 where R4 represents lower alkyl and R5 represents xe2x80x94OCH2 (optionally substituted phenyl).
The following compounds also form part of the invention. In the Tables 1-1, 1-2 and 1-3 it will be understood that Me means methyl; Et means ethyl; n-Pr means n-propyl; i-Pr means isopropyl; c-Pr means cyclopropyl; n-Bu means n-butyl; s-Bu means sec-butyl; i-Bu means isobutyl; t-Bu means tert-butyl; c-Bu means cyclobutyl; c-Pen means cyclopentyl; n-Hex means n-hexyl; c-Hex means cyclohexyl; Ph means phenyl; Bn means benzyl; CHCCH2 means prop-2-ynyl and CHCCH2CO means but-3-yn-1-oyl. Also where numbers appear directly after atoms or groups they are understood to be subscripts (e.g. CO2Me means CO2Me, CF3 means CF3 etc.).
Tables 1-1, 1-2 and 1-3 contain a total of five sets of compounds identified as follows:
Table 1-1 contains a set of 404 compounds having compound numbers from 1.1 to 1.404.
Table 1-2 contains two sets of compounds, the first set comprising of 727 compounds wherein Axe2x80x2 represents OR3 and having compound numbers from 2.1 to 2.727. The second set comprising of a further 727 compounds wherein Axe2x80x2 represents SR3 and having compound numbers from 3.1 to 3.727.
Table 1-3 contains two sets of compounds, the first set comprising of 720 compounds wherein Axe2x80x2 represents A-1 and having compound numbers from 4.1 to 4.720. The second set comprising of a further 720 compounds wherein Axe2x80x2 represents A-2 and having compound numbers from 5.1 to 5.720. Furthermore it is understood that the compounds in the following tables may represent either the Z or the E isomers at the double bond of formula (I) which is substituted by the OR1 group, or represents a mixture of both isomers.
Compounds of formula (I) above may be prepared by the application or adaptation of known methods (i.e. methods heretofore used or described in the literature).
It is to be understood that in the descriptions of the following processes the sequences may be performed in different orders, and that suitable protecting groups may be required to achieve the compounds sought.
According to a feature of this present invention compounds of formula (I-1) wherein R1, R2 and Xn are as defined above in the general formula (I), and B represents a halogen atom, may be prepared by the reaction of a compound of general formula (III): 
wherein R1, R2 and Xn are as defined above, with a suitable halogenating agent generally in an inert solvent or with no solvent, optionally with a radical initiator, and optionally in the presence of light. Suitable halogenating agents are for example, chlorine, bromine, N-bromosuccinimide, N-chlorosuccinimide or N-iodosuccinimide. Although there is no special limitation for the proportion of a halogenating agent to a compound of formula (III), it is convenient to use the halogenating agent in the range from 0.5 to 2 moles, more preferably 0.9 to 1.1 moles per mole of compound of formula (III).
Suitable radical initiators are for example, benzoylperoxide or azobisisobutyronitrile. Suitable solvents are for example, aliphatic hydrocarbons such as pentane, hexane, heptane or octane; aromatic hydrocarbons such as benzene; halogenated hydrocarbons such as dichloromethane, chloroform or dichloroethane. These solvents can be used alone or in admixture.
The reaction temperature is generally in the range from xe2x88x9280 C. to 150 C. or the boiling point of solvent used. The reaction time is generally in the range from 0.1 to 24 hours.
According to a further feature of this present invention compounds of formula (I-2): 
wherein R1, R2 and Xn are as defined above in the general formula (I), and Axe2x80x2 represents OR3, SR3, A-1 or A-2, wherein R1, R2, A-1 and A-2 are as defined above, and R3 represents optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted cycloalkenyl, xe2x80x94CpH2p (optionally substituted phenyl), xe2x80x94CqH2q (optionally substituted heteroaryl), xe2x80x94(CrH2r) CO2alkyl, xe2x80x94(CsH2s) cycloalkyl, xe2x80x94(CuH2u) COCH2 (optionally substituted phenyl), xe2x80x94(CfH2f) O (optionally substituted phenyl), xe2x80x94(CgH2g) S (optionally substituted phenyl), or xe2x80x94(CjH2j) O (CzH2z)(optionally substituted phenyl);
may be prepared by the reaction of a compound of general formula (I-1) wherein, Xn, R1 and R2 are as defined above, and B represents a halogen atom, with a compound of formula (IV). In the case where Axe2x80x2 represents A-2 the compound Axe2x80x2H is the amide R4C(xe2x95x90O)NHR5 when the alkylation reaction to give (I-2) occurs on the oxygen atom of the amide. The reaction is generally performed in a suitable solvent or without solvent, and preferably in the presence of an acid binding agent. Suitable acid binding agents are for example alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or calcium hydroxide; alkali or alkaline earth metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate, cesium carbonate, calcium carbonate, sodium bicarbonate or potassium bicarbonate; alkali metal hydrides such as sodium hydride or potassium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide or potassium tert-butoxide; or organic bases such as pyridine, triethylamine, 4-N,N-dimethylaminopyridine, diazabicycloundecene or diazabicylooctane. The molar ratio of the compound of formula (IV) to the compound of formula (I-1) is preferably in the range from 0.5 to 2 moles and more preferably from 0.9 to 1.1 moles. Suitable solvents are for example aliphatic hydrocarbons such as pentane, hexane, heptane or octane; aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform or dichloroethane; alcohols such as methanol, ethanol or isopropanol; esters such as methyl acetate or ethyl acetate; nitrites such as acetonitrile or propionitrile; N,N-dimethylformamide, dimethylsulfoxide or water. The reaction temperature is generally in the range from xe2x88x9280 C. to 150 C. or the boiling point of solvent used. The reaction time is generally in the range of 0.1 to 24 hours.
According to a further feature of this present invention the E-isomers conforming to formula (VI): 
wherein R1, R2, R4, R5 and Xn are as defined above in the general formula (I), may be prepared by isomerisation of the corresponding Z isomers conforming to formula (V): 
The isomerisation of the Z isomers of formula (V) to give the E isomers of formula (VI) may be performed using an acid. Suitable acids for the reaction are for example organic acid such as formic acid, acetic acid, propionic acid or trifluoroacetic acid; sulfonic acids such as benzenesulfonic acid or paratoluenesulfonic acid; or inorganic acids such as hydrochloric acid, sulfuric acid or hydrobromic acid. Suitable solvents are for example aliphatic hydrocarbons such as pentane, hexane, heptane or octane; aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform or dichloroethane; alcohols such as methanol, ethanol or isopropanol; esters such as methyl acetate or ethyl acetate; nitriles such as acetonitrile or propionitrile; or N,N-dimethylformamide, dimethylsulfoxide or water. The solvents can be used alone or in admixture. The reaction temperature is generally from xe2x88x9280 C. to 150 C. or the boiling point of the solvent used. The reaction time is generally in the range from 0.1 to 24 hours.
According to a further feature of this present invention compounds of formula (I-4): 
wherein R1, R2 and Xn are as defined above in the general formula (I), may be prepared by the hydrolysis of a compound of general formula (I-3): 
wherein, R1, R2 and Xn are as defined and R represents an alkyl group preferably lower alkyl for example methyl or ethyl.
The hydrolysis is generally performed in the presence of a base. Suitable bases are for example alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or calcium hydroxide; or alkali or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate or calcium carbonate. The proportion of base to compound of formula (I-3) is generally from 1.0 to 10 moles of base per mole of compound of formula (I-3). Suitable solvents include water optionally in admixture with alcohols such as methanol or ethanol, and ethers such as dioxan or tetrahydrofuran. The reaction temperature is generally from xe2x88x9280 C. to 150 C. or boiling the point of solvent used (preferably from 0 C. to 50 C.).
According to a further feature of this present invention compounds of formula (I) wherein R1, R2 and Xn are as defined above and A represents OR3 or SR3 wherein R3 represents optionally substituted lower alkylcarbonyl, optionally substituted lower alkenylcarbonyl, optionally substituted lower alkynylcarbonyl, optionally substituted cycloalkylcarbonyl, optionally substituted phenylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted cycloalkenylcarbonyl or xe2x80x94CO(CtH2t) Y and Y is as defined above, may be prepared by the acylation of the corresponding compound of formula (I) wherein A represents OH or is replaced by SH. The reaction is generally performed using an acid halide (preferably chloride) of formula (VII):
R3COWxe2x80x83xe2x80x83(VII)
wherein W represents a halide group, in an inert solvent such as dichloromethane or tetrahydrofuran at a temperature of from 0 to 80 C.
According to a further feature of this present invention compounds of formula (I) wherein R1, R2, Xn are as defined above and A represents a group S(O)kR3 wherein k is one or two may be prepared by the oxidation of the corresponding compounds in which k represents zero or one. The reaction is generally performed using an oxidant such as m-chloroperbenzoic acid in a solvent such as chloroform at a temperature of from 0 to the reflux temperature of the solvent.
Intermediates of formula (III) may be prepared by the alkylation of compounds of formula (VIII) which are in tautomeric equilibrium with compounds of formula (VIIIa): 
using an alkylating agent of formula R1Q wherein Q represents a leaving group such as a halide (preferably iodide) or for example dialkylsulfate of formula (R1)2SO4, generally in the presence of a base such as potassium carbonate, in a solvent such as N,N-dimethylformamide or acetone at 0-80 C. Compounds of formula (III) are novel and as such form a further feature of the present invention.
Intermediates of formula (VIII) may be prepared by the formylation of phenoxyacetic acid derivatives of formula (IX): 
generally using an alkyl formate of formula (X):
HCO2Raxe2x80x83xe2x80x83(X)
wherein Ra represents lower alkyl preferably methyl or ethyl, generally in the presence of a base such as sodium hydride or an alkali metal alkoxide such as sodium methoxide, in a solvent such as tetrahydrofuran or N,N-dimethylformamide at a temperature of from 0-80 C.
Intermediates of formula (I) wherein A is replaced by a group SH may be prepared by the reaction of the corresponding compound of formula (I-1) wherein B represents a halogen atom preferably bromide, with a thiolating agent for example sodium hydrosulfide, according to methods described in the references cited in Advanced Organic Chemistry, third edition by Jerry March, page 360.
Compounds of formula (IV), (VII), (IX) and (X) are known or may be prepared by known methods. Compounds of formula (I-3) may be prepared according to the above method for the preparation of compounds of formula (I) wherein A represents OR3 and R3 represents lower alkylcarbonyl.
The following Examples illustrate the preparation of compounds of formula (I). It is to be understood that the present invention is not limited by these examples. All of the compounds described in the following Preparative Examples and in Table 2 are the Z isomers (at the double bond which is substituted by the OR1 group).